Human Immunodeficiency Virus (HIV) is a major cause of morbidity and mortality in both the developed and the developing world. HIV is a retrovirus that causes acquired immunodeficiency syndrome (AIDS) in humans, which in turn allows life-threatening infections and cancers to thrive as the immune system progressively fails.
HIV infection typically occurs through the transfer of bodily fluids, such as blood, semen, vaginal fluid, pre-ejaculate, or breast milk, from one individual to another. HIV may be present within these bodily fluids as either the free virus, or as a virus present within the infected immune cells. HIV-1 tends to be the most virulent form of HIV, and is transmitted as a single-stranded enveloped RNA virus which, upon entry into a target cell, is converted into double-stranded DNA by reverse transcription. This DNA may then become integrated into the host's DNA where it can reside in a latent from and avoid detection by the immune system. Alternatively, this DNA may be re-transcribed into RNA genomes and translated to form viral proteins that are released from cells as new virus particles, which can then spread further.
Treatments of HIV, particularly HIV-1, commonly involve combination therapy with a co-formulation of lopinavir (LPV) and ritonavir (RTV). Such co-formulations are currently sold commercially as either film coated tablets or an oral solution both under the trade name Kaletra®. Lopinavir and Ritonavir are both protease inhibitors (PI) widely used in antiretroviral therapy. However, Ritonavir is no longer commonly used for its own antiretroviral activity but rather to boost the activity of other protease inhibitors, such as Lopinavir. In particular, Ritonavir is used to inhibit liver enzymes (e.g. cytochrome P450-3A4-CYP3A4) responsible for metabolising protease inhibitors such as lopinavir. Such metabolism inhibition allows for higher blood plasma concentrations of protease inhibitors such as Lopinavir, thereby allowing lower doses of Lopinavir to be administered. This in turn reduces the adverse side effects associated with high doses of Lopinavir.

Although current co-formulations of lopinavir and ritonavir are effective in prolonging life expectancy in HIV suffers, there remain a number of drawbacks associated with the currently available formulations.
Lopinavir acts on an intracellular target, so the ability of lopinavir to penetrate and accumulate within cells is a prerequisite for effective treatment (Owen and Khoo, Journal of HIV Therapy, 2004, 9(4), 53-57). One particular problem with the current formulations of lopinavir and ritonavir is that the penetration of lopinavir into cells is variable and inadequate both within and between patients. As cellular penetration and accumulation of the drug is necessary in order to effectively treat the HIV infected cells, there is a need for combination formulations of lopinavir and ritonavir that exhibit good levels of cellular accumulation, particularly in immune cells (e.g. macrophages and CD4+ lymphocytes).
In addition, the distribution of lopinavir throughout the body is also not uniform with current LPV/RTV co-formulations, and certain target tissues and sanctuary sites, such as the brain and the testis, suffer from poor exposure to the lopinavir. This can lead to sub-therapeutic levels of the drug reaching certain tissues, with the consequential effect that HIV infected cells residing in these tissues may not be adequately treated. Furthermore, resistance to lopinavir is becoming an increasing problem (Goshn et al., AIDS, 2009, 11, 165-173) and exposure to sub-therapeutic levels of lopinavir in these tissues increases the risk that lopinavir-resistant strains of HIV can arise and reseed the blood. Resistant strains of HIV are also transmittable meaning that individuals can be newly infected with resistant virus. There is, therefore, a need for LPV/RTV formulations that provide an improved distribution of lopinavir throughout the body, and in particular to sanctuary sites for the virus.
A further problem with current LPV/RTV co-formulations is that it is necessary to administer large doses of lopinavir each day (typically the adult dose is 400 mg/100 mg lopinavir/ritonavir twice daily), despite the “boost” effect provided by ritonavir. As a consequence, a patient will need to consume a large tablet or capsule of LPV/RTV or multiple smaller dosage tablets or capsules in order to obtain the required dosage. This can inevitably lead to problems with patient compliance. Furthermore, lopinavir treatment is also associated with a number of adverse side effects, which represent a major problem for patients, especially over prolonged periods (Delaugerre et al., Antimicrob. Agents Chemother., 2009, 53(7), 2934-2939). For these reasons, there is a need for more effective formulations of LPV/RTV, which in turn may enable the required dosage of lopinavir to be reduced. Lower doses could have an effect on the number and/or size of the tablets/capsules that need to be consumed by the patient, as well as prevalence of the adverse side effects.
A further problem with current LPV/RTV co-formulations is that the ratio of lopinavir/ritonavir is relatively low (typically 4:1) and thus doses of ritonavir are high. Ritonavir itself gives rise to adverse side effects and, in addition, detrimentally affects the efficacy of many other medications. This can lead to difficulties when certain other drugs are co-administered with ritonavir.
There is also a need for dosage forms that permit the dosage to be easily varied on a patient-by-patient basis depending on factors such as the age (including paediatric dosing) and weight of the patient, as well as the severity and stage of the infection.
It is therefore an object of the present invention to provide improved LPV/RTV co-formulations that address one or more of the drawbacks associated with the current LPV/RTV co-formulations.
In particular, it is an object of the invention is to provide a LPV/RTV co-formulations exhibiting good cell penetration and a more optimum and effective distribution throughout the body.
Another object of the present invention is to provide a LPV/RTV co-formulation with a high drug loading.
Another object of the present invention is to provide a formulation which permits lower overall dosage levels of either or both of lopinavir and ritonavir in HIV treatments.